5-substituted 3-aminoalkyl indoles

ABSTRACT

Compounds are disclosed of general formula (I) ##STR1## wherein R 1  represents a group CHO, COR 8 , CO 2  R 8 , CONR 9  R 10 , CSNR 9  R 10  or SO 2  NR 9  R 10 , 
     where R 8  represents an alkyl, cycloalkyl, aryl or aralkyl group, 
     R 9  represents a hydrogen atom or an alkyl group, and 
     R 10  represents a hydrogen atom or an alkyl, cyclo-alkyl, aryl or aralkyl group; 
     R 2 , R 3 , R 4 , R 6  and R 7 , which may be the same or different, each represents a hydrogen atom or a C 1-3  alkyl group; 
     R 5  represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or an aralkyl group or 
     R 4  and R 5  together form an aralkylidene group or 
     R 4  and R 5  together with the nitrogen atom to which they are attached form a saturated monocyclic 5- to 7-membered ring; and 
     Alk represents an alkylene chain containing two or three carbon atoms which may be unsubstituted or substituted by not more than two C 1-3  alkyl groups; 
     with the provisos that when R 4  and R 5  both represent alkyl groups R 1  does not represent the group CHO or COR 8  and that when R 4 , R 5 , R 6  and R 7  all represent hydrogen R 1  does not represent the group SO 2  NH 2  ; 
     and physiologically acceptable salts, solvates and bioprecursors thereof. The components are described as potentially useful for the treatment of migraine and may be formulated as pharmaceutical compositions in convention manner using one or more pharmaceutically acceptable carriers or excipients. Various processes for the preparation of the compounds are disclosed including, for example, reaction of an aminoalkyl indole with an acid of formula R 1  OH or an acylating agent corresponding thereto or with an inorganic cyanate or an organic isocyanate or isothiocyanate in order to introduce the desired R 1  group at the 5-position on the indole nucleus.

This application is a continuation of application Ser. No. 711,152 filedMar. 13, l985, which is a continuation of Ser. No. 431,597 filed Sept.30, 1982, now abandoned, which is a continuation of Ser. No. 292,023filed Aug. 11, l981 now abandoned.

This invention relates to heterocyclic compounds, to processes for theirpreparation, to pharmaceutical compositions containing them and to theirmedical use.

The present invention provides an indole of the general formula (I):##STR2## wherein R₁ represents a group CHO, COR₈, CO₂ R₈, CONR₉ R₁₀,CSNR₉ R₁₀ or SO₂ NR₉ R₁₀,

where R₈ represents an alkyl, cycloalkyl, aryl or aralkyl group;

R₉ represents a hydrogen atom or an alkyl group and

R₁₀ represents a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkylgroup;

R₂, R₄, R₆ and R₇, which may be the same or different, each represents ahydrogen atom or a C₁₋₃ alkyl group;

R₅ represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or anaralkyl group or

R₄ and R₅ together form an aralkylidene group or

R₄ and R₅ together with the nitrogen atom to which they are attachedform a saturated monocyclic 5- to 7-membered ring; and

Alk represents an alkylene chain containing two or three carbon atomswhich may be unsubstituted or substituted by not more than two C₁₋₃alkyl groups;

with the provisos that when R₄ and R₅ both represent alkyl groups R₁does not represent the group CHO or COR₈ and that when R₄, R₅, R₆ and R₇all represent hydrogen, R₁ does not represent the group SO₂ NH₂ ;

and physiologically acceptable salts solvates (e.g. hydrates) andbioprecursors thereof.

The compounds according to the invention include all optical isomersthereof and their racemic mixtures.

Referring to the general formula (I) the alkyl groups may be straightchain or branched chain alkyl groups and they preferably contain from 1to 6 carbon atoms unless otherwise specified. The alkyl groupsrepresented by R₈ may be unsubstituted or substituted by one to threehalogen atoms e.g. flourine. The cycloalkyl groups preferably contain 5to 7 carbon atoms. The term aryl, used as such or in the term aralkyl,preferably means phenyl which may be unsubstituted or substituted by oneor more alkyl groups e.g. methyl, halogen atoms e.g. flourine, orhydroxy or alkoxy groups e.g. methoxy. The alkyl moiety of the aralkylgroups preferably contains 1 to 4 carbon atoms. The aralkylidene groupis preferably an arylmethylidene group. The alkenyl groups preferablycontain 3 to 6 carbon atoms.

Suitable physiologically acceptable salts of the indoles of generalformula (I) include acid addition salts formed with organic or inorganicacids for example hydrochlorides, hydrobromides, sulphates, fumaratesand maleates. Other salts may be useful in the preparation of compoundsof formula (I) e.g. creatinine sulphate adducts.

The term "bioprecursors" used herein means compounds which have astructure different from that of the compound of formula (I) but which,upon administration to an animal or human being, are converted in thebody to a compound of formula (I).

The compounds of the invention mimic methysergide in contracting thedog, isolated saphenous vein strip (E. Apperley et al., Br. J.Pharmacol., 1980, 68, 215-224) and, like methysergide, they have littleeffect on blood pressure in the DOCA Hypertensive rat. Methysergide isknown to be useful in the treatment of mirgraine and produces aselective increase in carotid vascular resistance in the anaesthetiseddog; it has been suggested (P. R. Saxena., Eur. J. Pharmacol, 1974, 27,99-105) that this is the basis of its efficacy. Those compounds which wehave tested show a similar effect in the anaesthetised dog and thecompounds according to the invention are thus potentially useful for thetreatment of migraine.

Accordingly, the invention also provides a pharmaceutical compositionadapted for use in human medicine which comprises at least one compoundof general formula (I), a physiologically acceptable salt, solvate (e.g.hydrate) or a bioprecursor thereof and formulated for administration byany convenient route. Such compositions may be formulated inconventional manner using one or more pharmaceutically acceptablecarriers or excipients.

Thus, the compounds according to the invention may be formulated fororal, buccal, parenteral or rectal administration or in a form suitablefor administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycollate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterisation techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glyceride.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs or a nebuliser, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of a compound ofthe invention and a suitable powder base such as lactose or starch.

A proposed dose of the compounds of the invention for oral, parenteralor buccal administration to man for the treatment of migraine is 0.1 to100 mg of the active ingredient per unit dose which could beadministered, for example 1 to 4 times per day.

Aerosol formulations are preferably arranged so that each metered doseor "puff" of aerosol contains 20 μg-1000 μg of the compound of theinvention. The overall daily dose with an aerosol will be within therange 100 μg-10 mg. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses eachtime. The overall daily dose and the metered dose delivered by capsulesand cartridges in an inhaler or insufflator could be double those withaerosol formulations.

A preferred class of compounds represented by the general formula (I) isthat wherein Alk represents an unsubstituted alkylene chain containingtwo carbon atoms. Another preferred class of compounds of generalformula (I) is that wherein R₄ and R₅ each represents a hydrogen atom ora methyl or ethyl group and R₆ and R₇ each represents a hydrogen atom.It is preferred that the total number of carbon atoms in R₄ and R₅together does not exceed two.

A further preferred class of compounds of general formula (I) is wherein

R₂ represents a hydrogen atom or a methyl group.

A preferred class of compounds according to the invention is representedby the general formula (Ia): ##STR3## wherein R_(1a) represents a groupCHO, CONH₂, COR_(8a) or CO₂ R_(8a), where R_(8a) is an alkyl groupcontaining 1 to 4 carbon atoms, e.g. a methyl, ethyl or isobutyl group,or a trifluoromethyl group;

R_(2a) represents a hydrogen atom or a methyl group; and

R_(4a) and R_(5a), which may be the same or different, each represents ahydrogen atom or a methyl or ethyl group (with the provisos that thetotal number of carbon atoms in R_(4a) and R_(5a) together does notexceed two and that when R_(1a) represents a group CHO or a groupCOR_(8a)

then R_(4a) represents a hydrogen atom), and physiologically acceptablesalts, solvates (e.g. hydrates) or bioprecursors thereof.

A particularly preferred class of compounds according to the inventionis represented by the general formula (Ib): ##STR4## wherein R_(1b)represents a group CHO, CONH₂ or CO₂ R_(8b) wherein R_(8b) is a methyl,ethyl or isobutyl group;

R_(2b) represents a hydrogen atom or a methyl group; and

R_(4b) and R_(5b), which may be the same or different, each represents ahydrogen atom or a methyl or ethyl group (with the provisos that thetotal number of carbon atoms in R_(4b) and R_(5b) together does notexceed two and that when R_(1b) is the group CHO,R_(4b) represents ahydrogen atom), and physiologically acceptable salts, solvates (e.g.hydrates) and bioprecursors thereof.

According to another aspect of the invention, compounds of generalformula (I) and physiologically acceptable salts, solvates (e.g.hydrates) or bioprecursors thereof, may be prepared by the generalmethods outlined below. In the following processes, R₁, R₂, R₄, R₅, R₆,R₇ and Alk are as defined for the general formula (I), unless otherwisespecified.

According to one general process (A), a compound of general formula (I)may be prepared by reacting a compound of general formula (II); ##STR5##or a protected derivative thereof, with a suitable reagent which servesto introduce the group R₁.

Suitable reagents which serve to introduce the group R₁ include acids offormula R₁ OH or acylating agents corresponding thereto, inorganiccyanates, appropriate organic isocyanates or organic isothiocyanates.

Acylating agents which may conveniently be employed in the above processinclude acid halides (for example acid chlorides and sulphamoylchlorides), alkyl esters (e.g. the methyl or ethyl ester), activatedesters (for example the 2-(1-methylpyridinyl)ester), symmetricalanhydrides or mixed anhydrides, haloformates (e.g. ethylchloroformate)or other activated carboxylic acid derivatives such as thoseconventionally used in peptide synthesis.

The process may be effected in a suitable aqueous or non-aqueousreaction medium, conveniently at a temperature of from -70° to -150° C.Thus, the process using an activated ester or an anhydride may beeffected in a suitable reaction medium such as an amide (e.g.dimethylformamide), an ether (e.g. tetrahydrofuran), a nitrile (e.g.acetonitrile), a haloalkane (e.g. dichloromethane) or a mixture thereof,optionally in the presence of a base, such as pyridine or a tertiaryamine such as triethylamine. The reaction is preferably effected at atemperature of from -5° to +25° C.

The reaction using an alkyl ester may be effected in a suitable reactionmedium such as an alcohol (e.g. methanol), an amide (e.g.dimethylformamide), an ether (e.g. tetrahydrofuran) or a mixture thereofand conveniently at a temperature of from 0° to 100° C. When the reagentis an inorganic cyanate, an organic isocyanate or an organicisothiocyanate the reaction may be carried out in water, an alcohol(e.g. ethanol), an amide (e.g. dimethylformamide) an ether (e.g.tetrahydrofuran) or a mixture thereof, optionally in the presence of abase such as pyridine or a tertiary amine such as triethylamine andconveniently at a temperature of from 0° to 100° C.

Acids of formula R₁ OH may themselves be used in the preparation ofcompounds of formula (I). The reaction with such an acid is desirablyconducted in the presence of a coupling agent, for example carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide. The reaction may becarried out in a suitable reaction medium such as a haloalkane (e.g.dichloromethane), a nitrile (e.g. acetonitrile), an amide (e.g.dimethylformamide) or an ether (e.g. tetrahydrofuran) conveniently at atemperature of from -5° to +30° C. The reaction may also be carried outin the absence of a coupling agent in a suitable reaction medium such asa hydrocarbon (e.g. toluene or xylene) conveniently at a temperature offrom 50° to 120° C.

A compound of general formula (I) wherein R₁ represents --CHO may beprepared by heating a compound of general formula (II) in formic acid,preferably at reflux.

In a particular embodiment of this process, a compound of formula (I)wherein, R₁ represents the group --CONR₉ R₁₀ or --CSNR₉ R₁₀, may also beprepared by reaction of a compound of formula (II), or protectedderivative thereof, with phosgene or thiophosgene followed by anappropriate amine of formula R₉ R₁₀ NH.

The reaction is conveniently carried out in an inert organic solvent,such as an aromatic hydrocarbon (e.g. toluene).

Some starting compounds of general formula (II) wherein R₂ is hydrogen,may be prepared by reduction of a corresponding compound having anappropriate reducible group as the 5-position substituent such as --CNor ##STR6## using for example, lithium aluminium hydride.

According to another general process (B), compounds of general formula(I) may be prepared by cyclisation of a compound of general formula(III): ##STR7## wherein Q is the group NR₄ R₅ (or a protected derivativethereof) or a leaving group such as halogen (e.g. chlorine), acetate,tosylate or mesylate.

Suitable cyclisation methods are referred to in "A Chemistry ofHeterocyclic Compounds -- Indoles Part 1", Chapter II, edited by W. J.Houlihan (1972) Wiley Interscience, NY. Particularly convenientembodiments of the process are described below.

When Q is the group NR₄ R₅ (or a protected derivative thereof), theprocess is desirably carried out in an aqueous reaction medium, such asan aqueous alcohol (for example methanol) in the presence of an acidcatalyst. (In some cases the acid catalyst may also act as the reactionsolvent). Suitable acid catalysts include inorganic acids such assulphuric or hydrochloric acid or organic carboxylic acids such asacetic acid. Alternatively the cyclisation may be carried out in thepresence of a Lewis acid such as zinc chloride in ethanol or borontrifluoride in acetic acid. The reaction may conveniently be carried outat temperatures of from 20° to 200° C., preferably 50 ° to 125° C.

When Q is a leaving group such as chlorine, the reaction may be effectedin an aqueous organic solvent, such as an aqueous alcohol (e.g.methanol, ethanol or isopropanol), in the absence of a mineral acid,conveniently at a temperature of from 20° to 200° C., preferably 50° to125° C. This process results in the formation of a compound of formula(I) wherein R₄ and R₅ are both hydrogen atoms.

According to a particular embodiment of this process compounds ofgeneral formula (I) may be prepared directly by the reaction of acompound of general formula (IV): ##STR8## or a salt thereof with acompound of formula (V)

    R.sub.6 COCH.sub.2 AlkQ                                    (V)

wherein Q is as defined above or a salt or protected derivative thereof(such as an acetal or ketal e.g. formed with an appropriate alkylorthoformate), using the appropriate conditions as described above.

Compounds of formula (III) may be isolated as intermediates during theprocess for the preparation of compounds of general formula (I) whereina compound of formula (IV), or a salt or protected derivative thereof,is reacted with a compound of formula (V) or a salt or protectedderivative thereof, in a suitable solvent, such as an aqueous alcohol(e.g. methanol) and at a temperature of, for example, from 20° to 30° C.If an acetal or ketal of a compound of formula (V) is used, it may benecessary to carry out the reaction in the presence of an acid (forexample, acetic or hydrochloric acid). As illustrated in the followinggeneral processes (C) and (D), the aminoalkyl substituent --AlkNR₄ R₅may be introduced at the 3-position by a variety of conventionaltechniques which may, for example, involve modification of a substituentat the 3-position or direct introduction of the aminoalkyl substituentinto the 3-position.

Thus a further general method (C) for preparing compounds of generalformula (I) involves reacting a compound of formula (VI): ##STR9##(wherein Y is a readily displaceable group) or a protected derivativethereof, with an amine of formula R₄ R₅ NH.

The displacement reaction may conveniently be carried out on thosecompounds of general formula (VI) wherein the substituent group Y is ahalogen atom (e.g. chlorine, bromine or iodine) or a group OR where ORis an acyloxy group, such as acetoxy, chloroacetoxy, dichloroacetoxytrifluoroacetoxy or p-nitrobenzoyloxy or a sulphonate group (e.g.p-toluene sulphonate).

The above reaction is conveniently effected in an organic solvent(optionally in the presence of water), examples of which includealcohols, e.g. ethanol; ethers, e.g. tetrahydrofuran; esters e.g. ethylacetate; amides e.g. N,N--dimethylformamide; and ketones e.g. acetone,at a temperature of from -10° to +150° C., preferably 20° to 50° C.

The compounds of formula (VI) wherein Y is a halogen atom may beprepared by reacting a hydrazine of general formula (IV) with analdehyde or ketone (or protected derivative thereof) of general formula(V) in which Q is a halogen atom, in an aqueous alkanol (e.g. methanol)containing an acid (e.g. acetic or hydrochloric acid) or by treating acompound of general formula (VI) wherein Y is a hydroxyl group with theappropriate phosphorous trihalide. The intermediate alcohol where Y is ahydroxyl group may also be used to prepare compounds of formula (VI)wherein Y is the group OR by acylation or sulphonylation with theappropriate activated species (e.g. an anhydride or sulphonyl chloride)using conventional techniques. The intermediate alcohol may be preparedby cyclisation of a compound of formula (III) wherein Q is a hydroxylgroup (or a protected derivative thereof) using standard conditions.

Compounds of general formula (I) may also be prepared by another generalprocess (D) which comprises reducing a compound of general formula(VII): ##STR10## wherein W is a group capable of being reduced to givethe required AlkNR₄ R₅ group or a protected derivative thereof or a saltor protected derivative thereof.

The required Alk and NR₄ R₅ groups may be formed by reduction stepswhich take place separately or together in any appropriate manner.

Groups which may be reduced to the group Alk include correspondingunsaturated groups and corresponding groups containing either a hydroxylgroup or a carbonyl function.

Groups which may be reduced to the group NR₄ R₅ where R₄ and R₅ are bothhydrogen include nitro, azido, hydroxyimino and nitrile groups.Reduction of a nitrile group yields the group CH₂ NH₂ and thus providesa methylene group of the group Alk.

The required NR₄ R₅ groups wherein R₄ and/or R₅ are other than hydrogenmay be prepared by reduction of a nitrile (CHR₁₁)_(x) CHR₁₂ CN or analdehyde (CHR₁₁)_(x) CHR₁₂ CHO (where R₁₁ and R₁₂, which may be the sameor different, each represents a hydrogen atom or a C₁₋₃ alkyl group andx is zero or 1) in the presence of an amine, R₄ R₅ NH. Alternatively theR₄ R₅ NH group may be prepared by reaction of the corresponding compoundwherein R₄ and/or R₅ represent hydrogen with an appropriate aldehyde orketone in the presence of a suitable reducing agent. In some instances(e.g for the introduction of the group R₅ where R₅ is benzyl) thealdehyde (e.g. benzaldehyde) may be condensed with the amine and theintermediate thus formed may subsequently be reduced using a suitablereducing agent.

Examples of groups represented by the substituent group W include thefollowing: THO₂ (where T is Alk or an alkenyl group corresponding to thegroup Alk); AlkN₃ ; (CHR₁₁)_(x) CHR₁₂ CN; COCHR₁₂ Z; (CHR₁₁)_(x) CR₁₂═NOH; or CH(OH)CHR₁₂ NR₄ R₅ (where R₁₁, R₁₂ and x are as previouslydefined and Z is an azido group N₃ or the group NR₄ R₅ or a protectedderivative thereof).

It will be appreciated that the choice of reducing agent and reactionconditions will be dependent on the nature of the group W and othergroups already present on the molecule.

Suitable reducing agents which may be used in the above process includehydrogen in the presence of a metal catalyst (except wherein R₁ is thegroup CSNR₉ R₁₀), an alkali metal borohydride or cyanoborohydride, e.g.sodium borohydride or cyanoborohydride (except wherein W contains anitrile or hydroxyimino group) or a metal hydride, e.g. lithiumaluminium hydride (wherein R₁ is the group CSNR₉ R₁₀ and one of R₂, R₉and R₁₀ is hydrogen).

The metal catalyst may, for example be Raney Nickel or a noble metalcatalyst, such as platinum, platinum oxide, palladium or rhodium, whichmay be supported, for example, on charcoal or kieselguhr. In the case ofRaney nickel, hydrazine may also be used as the source of hydrogen.

Reduction in the presence of hydrogen and a metal catalyst mayconveniently be carried out in a solvent such as an alcohol e.g.ethanol, an ether e.g. dioxan or tetrahydrofuran or an ester e.g. ethylacetate at a temperature of from -10° to +50° C., preferably -5° to +30°C. The alkali metal borohydride or cyanoborohydride reduction mayconveniently be carried out in an alcohol such as propanol or ethanoland at a temperature of from 0° to 100° C. In some instances theborohydride reduction may be carried out in the presence of cobaltouschloride. The metal hydride reduction may be carried out using an ether,e.g. tetrahydrofuran as solvent and conveniently at a temperature offrom -10° to +100° C.

Particular embodiments of this process include the reduction of acompound of formula (VII) wherein W is the group CHR₁₂ CN, CHR₁₁ CHR₁₂NO₂, CH═CR₁₂ NO₂ or CHR₁₁ CR₁₂═ NOH, for example, by catalytic reductionwith hydrogen, e.g. hydrogen in the presence of a catalyst such aspalladium, optionally in the presence of a mineral acid such ashydrochloric or sulphuric acid.

A second embodiment of the process involves, for example, the reductionof a compound of formula (VII) wherein W is the group CHR₁₂ CN in thepresence of an amine HNR₄ R₅ using hydrogen in the presence of acatalyst such as palladium, except that R₁ may not be --CSNR₉ R₁₀.

According to a third embodiment, a compound of formula (VII) wherein Wis the group COCHR₁₂ Z may be reduced, preferably with heating, usingfor example, sodium borohydride in propanol. Where Z is an azido group,the process results in the formation of a compound of general formula(I) wherein R₄ and R₅ are both hydrogen atoms.

According to a fourth embodiment, a compound of formula (VII) wherein Wis the group AlkN₃ or CH(OH)CHR₁₂ NR₄ R₅ may be reduced using forexample hydrogen in the presence of a catalyst (e.g. palladium) orsodium borohydride. These reducing agents are also suitable for thereductive alkylation of for example AlkNHR₅ in the presence of asuitable aldehyde or ketone.

The starting materials or intermediate compounds of general formula(VII) may be prepared by analogous methods to those described in UKPublished Pat. Application No. 2035310 and "A Chemistry of HeterocyclicCompounds-Indoles Part II", Chapter VI, edited by W. J. Houlihan (l972)Wiley Interscience, NY.

Compounds of formula (VII) wherein W is the group (CHR₁₁)_(x) CHR₁₂ CHOmay be prepared by oxidation (e.g. with Jones' reagent) of a compound ofgeneral formula (VI) wherein Y is a hydroxyl group. A compound ofgeneral formula (VII) wherein W is the group (CHR₁₁)_(x) CR₁₂ ═NOH maybe prepared by treatment of the corresponding aldehyde withhydroxylamine hydrochloride using standard conditions.

The intermediate compound of general formula (VII) wherein W is thegroup AlkN₃ may be prepared from a compound of general formula (VI)wherein Y is a halogen atom using standard procedures.

Standard reducing agents such as sodium borohydride may be used toprepare a compound of general formula (VII) wherein W is the groupCH(OH)CHR₁₂ NR₄ R₅ from the corresponding compound of formula (VII)wherein W is the group COCHR₁₂ NR₄ R₅.

The following reactions (E), in any appropriate sequence, may ifnecessary and/or desired, be carried out subsequent to any of the abovedescribed processes:

(i) conversion of one compound of general formula (I) or a salt orprotected derivative thereof into another compound of general formula(I);

(ii) removal of any protecting groups, and

(iii) conversion of a compound of general formula (I) or a salt thereofinto a physiologically acceptable salt, solvate (e.g. hydrate) orbioprecursor thereof.

Thus, a compound formula (I) according to the invention may be convertedinto another compound of the invention using conventional procedures.

For example, a compound of general formula (I) wherein R₂, R₄, R₅ and/orR₇ are alkyl groups may be prepared from the corresponding compounds offormula (I) wherein one or more of R₂, R₄, R₅ and R₇ represent hydrogen,by reaction with a suitable alkylating agent such as an alkyl halide,alkyl tosylate or dialkylsulphate. The alkylation reaction isconveniently carried out in an inert organic solvent such as an amide(e.g. dimethylformamide) an ether (e.g. tetrahydrofuran) or an aromatichydrocarbon (e.g. toluene) preferably in the presence of a base.Suitable bases include, for example, alkali metal hydrides, for examplesodium hydride, alkali metal amides, such as sodium amide, alkali metalcarbonates, such as sodium carbonate or an alkali metal alkoxide such assodium or potassium methoxide, ethoxide or t-butoxide.

A particularly suitable method for preparing a compound formula (I)wherein R₄ and/or R₅ is other than hydrogen, is reductive alkylation ofthe corresponding compound wherein R₄ and/or R₅ represents hydrogen,with an appropriate aldehyde or a ketone (e.g. benzaldehyde or acetone)in the presence of a suitable reducing agent. Alternatively the aldehydeor ketone may be condensed with the primary amine and the intermediatethus formed may subsequently be reduced using a suitable reducing agent.

It will be appreciated that the choice of reducing agents and reactionconditions depends upon the nature of the substituent groups alreadypresent on the compound of formula (I) which is to be alkylated.Suitable reducing agents which may be employed in this reaction includehydrogen in the presence of a metal catalyst, an alkali metalborohydride or cyanoborohydride (e.g. sodium borohydride orcyanoborohydride) using the conditions previously described or formicacid (using the carbonyl compound as reaction solvent, at a temperatureof from 0°-100° C., conveniently 0°-50° C.)

According to a further embodiment, a compound of general formula (I)where R₅ is a hydrogen atom, may be prepared by reduction of acorresponding compound of general formula (I) wherein R₅ is a benzylgroup, for example with hydrogen in the presence of a catalyst e.g. 10%palladium on carbon.

It should be appreciated that in some of the above transformations itmay be necessary or desirable to protect any sensitive groups in themolecule of the compound in question to avoid any undesirable sidereactions. For example, during any of the reaction sequences describedabove, it may be necessary to protect the group NR₄ R₅, wherein R₄and/or R₅ represent hydrogen, with a group easily removable at the endof the reaction sequence. Such groups may include, for example, aralkylgroups, such as benzyl, diphenylmethyl or triphenylmethyl; or acylgroups, such as N-benzyloxycarbonyl or t-butoxycarbonyl or phthaloyl.

In some cases, it may also be necessary to protect the indole nitrogenwherein R₇ is hydrogen.

Subsequent cleavage of the protecting group may be achieved byconventional procedures. Thus an aralkyl group such as benzyl, may becleaved by hydrogenolysis in the presence of a catalyst (e.g. palladiumon charcoal); an acyl group such as N-benzyloxycarbonyl may be removedby hydrolysis with, for example, hydrogen bromide in acetic acid or byreduction, for example by catalytic hydrogenation. The phthaloyl groupmay be removed by hydrazinolysis (e.g. by treatment with hydrazinehydrate) or by treatment with a primary amine (e.g. methylamine).

Where it is desired to isolate a compound of the invention as a salt,for example as an acid addition salt, this may be achieved by treatingthe free base of general formula (I), with an appropriate acid,preferably with an equivalent amount or with creatinine sulphate in asuitable solvent (e.g. aqueous ethanol).

The starting materials or intermediate compounds for the preparation ofthe compounds according to this invention may be prepared by analogousmethods to those described in UK Published Pat. Application No. 2035310.

As well as being employed as the last main step in the preparativesequence, the general methods indicated above for the preparation of thecompounds of the invention may also be used for the introduction of thedesired groups at an intermediate stage in the preparation of therequired compound. Thus, for example, the required group at the5-position may be introduced either before or after cyclisation to formthe indole nucleus. It should therefore be appreciated that in suchmulti-stage processes, the sequence of reactions should be chosen inorder that the reaction conditions do not affect groups present in themolecule which are desired in the final product.

The invention is further illustrated by the following examples. Alltemperatures are in °C.

Preparation 1 N-[3-(Cyanomethyl)-1H-indol-5-yl]formamide

A solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) in methyl formate(20 ml) was stirred at room temperature for 24 h. The resulting solidprecipitate was filtered off, washed with ether (2×20 ml) and dried invacuo to give the title compound (0.41 g) as a white microcrystallinesolid m.p. 196°6-200° (softens 194°).

Preparation 2 5-(Methylamino)-1H-indole-3-acetonitrile, quarter hydrate

A solution of 5-amino-1H-indole-3-acetonitrile (3.6 g) in triethylorthoformate (80 ml) containing trifluoroacetic acid (3 drops) wasrefluxed for 24 h. The solvent was evaporated in vacuo and the residuewas dissolved in absolute ethanol (50 ml), cooled to 0° C., treated withexcess sodium borohydride (4.5 g) and then refluxed for 5 h.

The cooled solution was then added to a mixture of 2N hydrochloric acid(400 ml) and ice, washed with ethyl acetate (2×100 ml) and the acidsolution was then basified (Na₂ CO₃) and extracted with ethyl acetate(2×200 ml). These combined extracts were dried (Na₂ SO₄), filtered, andthe solvent was evaporated in vacuo yielding a brown oil. Columnchromatography (Kieselgel 60, 250 g) eluting with ether afforded thetitle compound as a fawn solid (1.5 g) m.p. 120°-2°.

Preparation 32-[2-[5-(Aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione,hemisulphate, hydrate

A suspension of3-[2-(1,3-dihydro-1,3-dioxo-2H-isoiondol-2-y1)ethyl]-1H-indole-5-carbonitrile(4.7 g) in methanol (250 ml) and sulphuric acid (1.5 ml) washydrogenated at room temperature and pressure over 10% palladium oncharcoal (50% aqueous paste; 2.0 g) for 45 h. The catalyst was filteredoff, and the filtrate was evaporated to dryness, giving an orange oil,which was dissolved in hot water (70 ml). On cooling, the title compoundcrystallised as a cream solid (3.8 g) m.p. 235°-8°.

Preparation 4 Phenylmethyl[2-[5-(aminomethyl)-1H-indol-3-y1]ethyl]carbamate

(i) Phenylmethyl [2-[5-(hydroxymethyl)-1H-indol-3-yl]ethyl]-carbamate

A solution of3-[2-[[(phenylmethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylic acid(9 g) and carbonyldiimidazole (5.2 g) in dry tetrahydrofuran (THF) (150ml) was stirred vigorously under nitrogen at room temperature for 5 h. Asolution of lithium borohydride (1.6 g) in dry THF (70 ml) was addedover 70 min and the mixture then stirred for 18 h. Aqueous acetic acid(30%, 25 ml) was added slowly to the ice-cooled mixture and the solutionwas then partitioned between brine (25%, 300 ml) and ethyl acetate (250ml). The organic layer was washed with sulphuric acid (0.4M, saturatedwith sodium chloride, 3×80 ml), brine (100 ml) and potassium carbonatesolution (25%, 2×100 ml). The dried (MgSO₄) solution was evaporated invacuo, the residue taken up in dichloromethane (150 ml) and insolublematerial was filtered off. The filtrate was evaporated in vacuo to leavethe alcohol (9 g) as a colourless oil containing some (ca. 45 mole %)ethyl acetate. T.l.c. Si0₂ /Et₂ O, R_(f) 0.25.

(ii) Phenylmethyl [2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-carbamate

A solution of diethyl azodicarboxylate (1.48 g) in dry tetrahydrofuran(THF) (8 ml) was added over 2 min., keeping the temperature at 25°, to astirred solution of phenylmethyl[2-[5-(-hydroxymethyl)-1H-indol-3-yl]ethyl]-carbamate (2.6 g),triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml).After 4 h, the solvent was evaporated in vacuo and the residue wasdissolved in a solution of hydrazine hydrate (15 ml) in ethanol (100ml).

After 5 days the mixture was partitioned between sulphuric acid (0.5N,500 ml) and ethyl acetate (2×300 ml). The acid layer was basified withpotassium carbonate and the product was extracted into ethyl acetate(200 ml). The dried (Na₂ SO₄) extract was evaporated in vacuo to leavethe crude amino (0.7 g) as a brown oil which later solidified.Crystallisation from ethyl acetate gave the title compound (0.15 g) ascream coloured crystals m.p. 125.5°-.26.5°.

Example 1 Ethyl [3-(2-Aminoethyl)-1H-indol-5-yl] carbamate, compoundwith creatinine, sulphuric acid and water (2:2:2:1)

(i) Ethyl [3-(cyanomethyl)-1H-indol-5-yl] carbamate

A solution of 5-amino-1H-indole-3-acetonitrile (1.5 g) indimethyl-formamide (35 ml) was treated with potassium carbonate (4.2 g)and ethyl chloroformate (0.9 ml) added dropwise over 20 min. After afurther 5 min, the reaction mixture was poured into water (150 ml), leftfor 30 min and then extracted with ethyl acetate (3×130 ml). Thecombined ethyl acetate extracts were washed with water (2×150 ml), 8%sodium bicarbonate solution (2×150 ml) and water (2×100 ml) and dried(MgSO₄) and the solvent was removed under reduced pressure to afford abrown oil. The oil was crystallised from ethyl acetate and cyclohexaneto give the title compound (1.65 g) as a brown crystalline solid, m.p.119°-123°.

(ii) Ethyl [3-(aminoethyl)-1H-indol-5-yl]carbamate, compound withcreatinine, sulphuric acid and water (2:2:2:1)

Ethyl [3-(cyanomethyl)-1H-indol-5-yl]carbamate (1.5 g) was catalyticallyhydrogenated over 5% rhodium-on-alumina (0.5 g) in a mixture of ethanol(50 ml) and ammonia (0.6 ml) for 40 h at 40° then at 50° for a further 8h. The mixture was filtered through hyflo and evaporated to dryness toafford a brown oil. This oil was purified by column chromatography onsilica (25 g) using ethyl acetate/2-propanol/water/ammonia (25:15:4:1)as eluant to give a brown oil (0.58 g) which was dissolved in ethanoland treated with an aqueous solution of creatinine and sulphuric acid(1:1, 2M, 1 ml) to give an off-white solid which was recrystallised fromaqueous acetone to give the title compound as a colourless solid (0.65g) m.p. 184.5°-187.5°.

Analysis. Found: C,43.4; H,5.9; N,17.65. C₁₃ H₁₇ N₃ O₂.C₄ H₇ N₃ O.H₂SO₄.O.5H₂ O requires: C,43.7; H,5.8; N,18.0%.

Example 2 N-[3-(2-Aminoethyl)-1H-indol-5-yl]formamide, compound withcreatinine, sulphuric acid and water (1:1:1:1.3)

Hydrazine hydrate (30 ml) was added slowly over 3 h to a mixture ofN-[3-(cyanomethyl)-1H-indol-5-yl]formamide (1.0 g) and Raney nickel (2g) in ethanol (100 ml) at reflux under nitrogen. The catalyst wasfiltered off and the filtrate evaporated to an oil (l.1 g) which wasdissolved in a hot mixture of ethanol (60 ml) and water (30 ml) andtreated with a solution of creatinine sulphate (1.2 g) in water (4 ml).Dilution with ethanol (150 ml) precipitated the title compound as awhite solid (1.4 g) m.p. 175°-183°.

Analysis. Found: C,41.5; H5.6 N,18.7. C₁₁ H₁₃ N₃ O.C₄ H₇ N₃ O.H₂SO₄.1.3H₂ O requires: C,41.1; H,5.7; N.19.2%.

Example 3 N-[3-(2-Aminoethyl)-1H-indol-5-yl]-N-methylformamide, compoundwith creatinine, sulphuric acid and water (8:10:9:16)

(i) N-[3-(Cyanomethyl)-1H-indol-5-yl]-N-methylformamide

A solution of 5-(methylamino-1H-indole-3-acetonitrile (0.2 g) in methylformate (7 ml) was kept at room temperature for 36 h. The solvent wasevaporated in vacuo and the residue was partitioned between ethylacetate (10 ml) and hydrochloric acid (2N, 10 ml). The organic layer wasdried (Na₂ SO₄) and evaporated in vacuo yielding the title compound as afawn solid, (0.13 g) m.p. 118°-120° C.

(ii) N-[3-(2-Aminoethyl)-1H-indol-5-yl]-N-methylformamide compound withcreatinine, sulphuric acid and water (8:10:9:16)

Following the method described in Example 2,N-[3-(cyanomethyl)-1H-indol-5-yl]-N-methylformamide (1.2 g) in ethanol(150 ml) was reduced with Raney nickel (0.03 g) and hydrazine hydrate(23 ml) over 8 h. The title compound (1.4 g) was obtained as a buffsolid m.p. 208°-210° after creatinine sulphate formation.

Analysis. Found: C,40.8; H,5.6; N,18.7. C₁₂ H₁₅ N₃ O.1.25C₄ H₇ N₃O.1.125H₂ SO₄.2H₂ O requires: C,40.4; H,6.0; N,18.7%.

Example 4 Ethyl [3-(2-aminoethyl)-1H-indol-5-yl]methylcarbamate,compound with creatinine sulphuric acid and water (1:1:1:2)

(i) Ethyl [3-(cyanomethyl)-1H-indol-5-yl]methylcarbamate

Ethyl chloroformate (0.21 ml) was added dropwise to a stirred solutionof 5-(methylamino)-1H-indole-3-acetonitrile (0.4 g) in dimethylformamide(15 ml). After 10 min. the solution was diluted with water (30 ml),stirred for 30 min. and extracted with ethyl acetate (2×100 ml). Thecombined extracts were washed with 10% brine (2×100 ml), 8% sodiumbicarbonate (2×100 ml) and water (2×100 ml), dried (Na₂ SO₄) andevaporated in vacuo to yield the crude product as a brown oil.Trituration with ether gave a fawn solid (0.4 g). A sample wascrystallised from ether to give the title compound as a white solid m.p.104°-106°.

(ii) Ethyl [3-(2-aminoethyl)-1H-indol-5-yl]methylcarbamate, compoundwith creatinine, sulphuric acid, and water (1:1:1:2)

A solution of ethyl [3-(cyanomethyl)-1H-indol-5-yl]methylcarbamate (0.2g) in absolute ethanol (30 ml) containing concentrated hydrochloric acid(8 drops) was hydrogenated at room temperature and pressure overpalladium on charcoal (10%, 0.4 g) until hydrogen uptake ceased (8 h, 23ml). The catalyst was filtered off, washed with absolute ethanol, andthe filtrate evaporated in vacuo yielding a brown oil. The amine wasdissolved in a hot solution of ethanol and water (8:1, 18 ml) andtreated with an aqueous solution of creatinine and sulphuric acid (1:1,2M, 0.38 ml). Filtration of the cooled mixture gave the title compoundas a white solid m.p. 210°-212° (dec.) (0.15 g).

Analysis. Found: C,42.7; H,5.9; N,16.7. C₁₄ H₁₉ N₃ O₂.C₄ H₇ N₃ O.H₂SO₄.2H₂ O requires: C,42.5; H,6.3; N,16.5%.

Example 5 N-[3-(2-Aminoethyl)-1H-indol-5-yl]urea, compound withcreatinine, sulphuric acid and water (1:1:1:1)

(i) N-[3-(Cyanomethyl)-1H-indol-5-yl]urea

A solution of sodium cyanate (1.2 g) in water (10 ml) was added to astirred solution of 5-amino-1H-indole-3-aceto-nitrile (1.5 g) in glacialacetic acid (5 ml) and water (10 ml). Stirring was continued until abrown gum precipitated (10 min). The aqueous layer was then decantedoff, and extracted with ethyl acetate (2×100 ml). The combined extractswere washed with sodium carbonate soln. (2N, 2×100 ml), dried (Na₂ SO₄)and evaporated in vacuo to yield the crude urea as an off-white solid(0,3 g). The brown gum was purified by column chromatography (Kieselgel60, 25 g) using ethyl acetate as eluant to yield more of the crude urea(0.1 g). The crude urea was then crystallised from isopropanol to yieldthe title compound as a fawn solid (0.3 g) m.p. 200°-204°.

(ii) N-[3-(2-Aminoethyl)-1H-indol-5-yl]urea, compound with creatinine,sulphuric acid and water (1:1:1:1:).

Following the method of Example 2, N-[3-(cyanomethyl)-1H-indol-5-yl]urea(0.2 g) in ethanol (30 ml) was reduced with Raney nickel (0.03 g) andhydrazine hydrate (6 ml) over 5 h. The title compound (0.15 g) wasobtained as a cream solid m.p. 208°-12° after creatinine sulphateformation.

Analysis. Found: C,40.1; H,5.6; N,21.5; C₁₁ H₁₄ N₄ O.C₄ H₇ N₃ O.H₂SO₄.H₂ O. requires: C,40.3; H,5.6; N.21.9%.

T.l.c. Silica ethyl acetate/2-propanol/water/0.88 amonia (25:15:8:2)R_(f) O.44.

Example 6 Methyl[3-(2-aminoethyl)-1H-indol-5-yl]carbamate, compound withcreatinine, sulphuric acid and water (1:1:1:1).

(i) Methyl[3-(cyanomethyl)-1H-indol-5-yl]carbamate

Following the method of Example 4(i), 5-amino-1H-indole-3-acetonitrile(0.8 g) in dimethylformamide (10 ml) was reacted with methylchloroformate (0.5 ml) to give the title compound (0.44 g) as a whitesolid m.p. 146°-8° after column chromatography (Kieselgel 60, 100 g)eluted with ether.

(ii) Methyl [3-(2-aminoethyl)-1H-indol-5-yl]carbamate, compound withcreatinine, sulphuric acid, and water (1:1:1:1)

Following the method of Example 4 (ii)methyl[3-(cyanomethyl)-1H-indol-5-yl]carbamate (0.7 g) was hydrogenatedin ethanol (100 ml) over palladium on charcoal (10%, 1.0 g) for 24 h togive, after creatinine sulphate formation, the title compound (0.5 g) asa white solid m.p. 197°-200°.

Analysis. Found: C,41.4; H,5.7; N,18.1. C₁₂ H₁₅ N₃ O₂.C₄ H₇ N₃ O.H₂SO₄.H₂ O requires: C,41.55; H,5.7; N.18.2%.

Example 7 N-[3-[2-(Methylamino)ethyl]-1H-indol-5yl]formamide, compoundwith creatinine, sulphuric acid and water (10:12:11:20)

A solution of N-[3-(cyanomethyl)-1H-indol-5-yl]formamide (0.3 g) inabsolute ethanol (30 ml) containing methylamine, (33% in ethanol, 2 ml)was hydrogenated at room temperature and pressure over palladium oxideon charcoal (10%, 0.5 g) for 24 h until hydrogen uptake ceased (90 ml).The catalyst was filtered off, washed with absolute ethanol, and thefiltrate was evaporated in vacuo yielding a brown oil.

The amine was dissolved in a hot mixture of ethanol and water (8:1, 18ml) and an aqueous solution of creatinine and sulphuric acid (1:1, 2M,0.6 ml) was added. Filtration of the cooled mixture gave the titlecompound as an off-white solid (0.35 g) m.p. 205°-207°.

Analysis. Found: C,40.6: H,5.5: N,.18.8. C₁₂ H₁₅ N₃ O.1.2C₄ H₇ N₃O.1.1H₂ SO₄.2H₂ O requires: C,40.7; H,5.8; N.18.6%.

Example 8 N-[3-(2-Aminoethyl)-1H-indol-5-yl]acetamide, compound withcreatinine, sulphuric acid and water (2:3:2:5)

(i) N-[3-(Cyanomethyl)-1H-indol-5-yl]acetamide

Acetyl chloride (0.21 ml) was added dropwise to a stirred solution of5-amino-1H-indole-3-acetonitrile (0.5 g) and pyridine (0.24 ml) in dryacetonitrile (10 ml) at 0°-2° under nitrogen. When the addition wascomplete the solution was stirred at 0° for 30 minutes, poured intowater (50 ml) and extracted with ethyl acetate (3×25 ml). The combinedextracts were dried (MgSO₄), filtered and evaporated under reducedpressure to a brown solid (0.5 g) which was crystallised from anethanol-cyclohexane mixture to give the title compound (0.43 g) asoff-white needles, m.p. 171.5°-175°.

(ii) N-[3(2-Aminoethyl)-1H-indol-5-yl]acetamide, compound withcreatinine, sulphuric acid and water (2:3:2:5)

Following the method described in Example 2,N-[3-(cyanomethyl)-1H-indol-5-yl]acetamide (0.3 g) in ethanol (15 ml)was reduced with Raney nickel (0.06 g) and hydrazine hydrate (6.2 ml)over 6 h. The title compound was obtained as a white crystalline solidm.p. 177°-182°(dec).

Analysis. Found: C,40.6; H,5.7; N,20.1. C₁₂ H₁₅ N₃ O.1.5C₄ H₇ N₃ O.H₂SO₄.2.5H₂ O: C,40.8; H,6.2; N,19.8%.

The following compounds were prepared according to the method describedin Example 8(i) from 5-amino-1H-indole-3-acetonitrile and theappropriate acid chloride or acid anhydride as detailed in Table I.

Example 9 N-[3-(2-Aminoethyl)-1H-indol-5-yl]-2-methylpropanamide,compound with hydrogen chloride and water (4:4:3)

(ii) A solution of N-[3-(cyanomethyl)-1H-indol-5-yl]-2-methylpropanamide(0.4 g) in absolute ethanol (50 ml) containing concentrated hydrochloricacid (10 drops) was hydrogenated at room temperature and pressure overpalladium on charcoal (10%. 1.5 g) for 16 h, before the catalyst wasreplaced (10%, 1 g). After a further 4 h, when hydrogen uptake (75 ml)had ceased, the catalyst was

                                      TABLE I                                     __________________________________________________________________________         Wt. of starting                                                                              Vol. of                                                                             Vol. of                                                                            Vol. of                                                                            Wt. of                                         material       Reagent                                                                             pyridine                                                                           CH.sub.3 CN                                                                        product                                                                            Recrystallisation                                                                              m.p.                Ex. No.                                                                            (g)     Reagent                                                                              (ml)  (ml) (ml) (g)  solvent   Mol.                                                                                 (°C.)        __________________________________________________________________________     9 (i)                                                                             2.8     Pr.sup.i COCl                                                                        1.8   2    50   1.8  *         C.sub.14 H.sub.15                                                             N.sub.3 O                                                                            138-140             10 (i)                                                                             2.0     (CF.sub.3 CO).sub.2 O                                                                2.45  1    40   1.46 Ethyl     C.sub.12 H.sub.8                                                              F.sub.3 N.sub.3                                                                      165-6                                                        acetate/cyclohexane                  __________________________________________________________________________     *Purified by column chromatography on Kieselgel 60 (150 g) eluted with        ethyl acetate                                                            

filtered off, washed with absolute ethanol, and the filtrate wasevaporated in vacuo yielding a brown solid. The crude hydrochloride wascrystallised from a mixture of methanol and ethyl acetate, to give thetitle compound as a light brown solid (0.2 g) m.p. 274°-276°.

Analysis. Found: C,56.7; H,7.4; N,13.7. C₁₄ H₁₉ N₃ O.HCl.O.75H₂ Orequires: C,56.95; H,7.3; N,14.2%.

Example 10 N-[3-(2-Aminoethyl)-1H-indol-5-yl]trifluoroacetamide,compound with creatinine, sulphuric acid and water (1:1:1:2)

(ii) N-[3-(Cyanomethyl)-1H-indol-5-yl]trifluoroacetamide (1.3 g) inethanol (50 ml) and ammonia (0.6 ml) was hydrogenated at roomtemperature and pressure over rhodium-on-alumina (0.5 g) for 48 h. Themixture was filtered through hyflo and evaporated to dryness underreduced pressure to afford a brown oil. The brown oil was purified bycolumn chromatography (Kieselgel 60, 25 g) using a mixture of ethylacetate, 2-propanol, water and ammonia (25:15:4:1) as eluent. Theresulting solid was dissolved in hot ethanol and treated with an aqueoussolution of creatinine and sulphuric acid (2M, 1:1, 1 ml) and theresulting solid was recrystallised from aqueous acetone to give thetitle compound as a pinkish solid m.p. 186°-215° (dec).

Analysis. Found: C,37.2; H,5.05; N,16.2. C₁₂ H₁₂ F₃ N₃ O.C₄ H₇ N₃ O.H₂SO₄ 2H₂ O requires: C,37.1; H,4.9; N,16.2%.

Example 11 N-[3-(2-Aminoethyl)-1H-indol-5-yl]-N'-methylthiourea,compound with creatinine, sulphuric acid and water (1:1:1:1)

(i) N-[3-(Cyanomethyl)-1H-indol-5-yl]N'-methylthiourea, compound withethanol (2:1)

Methyl isothiocyanate (0.40 ml) was added to a stirred solution of5-amino-1H-indole-3-acetonitrile (l g) in dry acetonitrile (20 ml). Thesolution was stirred at room temperature for 3 days. A further quantityof methyl isothiocyanate (0.05 ml) was added and the mixture was heatedat 50° for 5 h. The solution was evaporated in vacuo to a viscous oilwhich solidified on trituration with an ethanolether mixture. Theresulting solid was filtered off and dried in vacuo to give the titlecompound (1.17 g) as an off-white crystalline solid, m.p. 103°-110°.

(ii) N-[3-(2-Aminoethyl)-1H-indol-5-yl]-N'-methylthiourea, compound withcreatinine, sulphuric acid and water (1:1:1:1)

Lithium aluminium hydride (0.19 g) was added in small portions at18°-20° to a stirred suspension ofN-[3-(cyanomethyl)-1H-indol-5-yl]-N'-methylthiourea (0.4 g) in drytetrahydrofuran (10 ml) under nitrogen. When the addition was completethe yellow suspension was heated at reflux for 2 h. The suspension wascooled to room temperature and the excess lithium aluminium hydride wasdestroyed by the careful addition of a water-ethanol mixture (1:1) (30ml). The resulting suspension was filtered off and the filtrate wasevaporated under reduced pressure to a yellow semi-solid. Ethanol (50ml) and water (10 ml) were added to the solution was filtered to removea small quantity of insoluble material. The filtrate was heated toreflux and treated with a hot solution of creatinine sulphate (0.6 g) inwater (2 ml). On cooling, the title compound was obtained as abuff-coloured solid m.p. 226°-9° (dec).

Analysis. Found: C,40.3; H,5.5; N,20.1. C₁₂ H₁₆ N₄ S.C₄ H₇ N₃ O.H₂SO₄.H₂ O requires: C,40.2; H,5.7; N,20.5%.

Example 12 N-[3-(2-Aminoethyl)-1H-indol-5-yl]thiourea, fumarate,hemihydrate

(i) Ethyl [[[3-(cyanomethyl)-1H-indol-5-yl]amino]thiocarbonyl]carbamate

Ethoxycarbonyl isothiocyanate (1.2 ml) was added dropwise to a stirredsolution of 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry acetonitrile(50 ml). After 10 min. the resulting suspension was diluted with water(40 ml) and stirred for 20 min.

The precipitate was filtered off, washed with dry acetonitrile, anddried in vacuo to give the title compound as a cream solid (1.5 g) m.p.201°-202 °C.

(ii) N-[3-(Cyanomethyl)-1H-indol-5-yl]thiourea

A solution of ethyl[[[3-(cyanomethyl)-1H-indol-5-yl]amino]thiocarbonyl]carbamate (0.5 g) in2N sodium hydroxide (3 ml) and ethanol (10 ml) was stirred at 40° C. for2 h. The resulting precipitate was filtered off, triturated with water(40 ml), washed with ethanol (ca. 30 ml) and dried in vacuo to give thetitle compound as a white solid. (0.25 g) m.p. 212°-214°C.

(iii) N-[3 -(2-Aminoethyl)-1H-indol-5-yl]thiourea, fumarate, hemihydrate

Lithium aluminium hydride (0.5 g) was added portion-wise, undernitrogen, to a stirred suspension ofN-[3-(cyanomethyl)-1H-indol-5-yl]thiourea (0.6 g) in THF (150 ml). Whenthe addition was complete aluminium chloride (1.74 g) was added, and theresulting grey suspension was stirred at reflux for 1 h.

The mixture was cooled in ice and excess reagent decomposed by cautiousaddition of 10% water in THF. Brine (100 ml) and ethyl acetate (100 ml)were added, insoluble material filtered off, and the aqueous layerextracted with ethyl acetate (100 ml).

The combined organic solutions were washed with brine (l00 ml), dried(Na₂ SO₄) and evaporated in vacuo to yield a pale yellow oil. The oilwas dissolved in a solution of fumaric acid (0.3 g) in methanol fumarateprecipitate by the addition of ethyl acetate (250 ml). The salt wascrystallised from isopropanol and recrystallised from a mixture ofmethanol and ethyl acetate to give the title compound as a cream solid(0.15 g) m.p. 147°-150°.

Analysis. Found: C,50.1; H,5.4; N,15.8. C₁₁ H₁₄ N₄ S.C₄ H₄ O₄.O.5H₂ Orequires: C,50.1; H,5.3; N,15.6%.

Example 13 2-methylpropyl [3(2-aminoethyl)-1H-indol-5-yl]carbamate,hydrochloride

(i) 2-Methylpropyl [3-(cyanomethyl-1H-indol-5-yl]carbamate, quarterhydrate

Isobutyl chloroformate (1.5 ml) was added dropwise to a stirred solutionof 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry DMF (20 ml). After 10min the solution was diluted with water (150 ml) and stirring continuedfor 30 min. The resulting solution was extracted with ethyl acetate(2×100 ml) and the combined extracts washed with brine (10%, 100 ml),water (100 ml), dried (Na₂ SO₄) and evaporated in vacuo to yield thecrude product as a brown oil. This was purified by column chromatography(Kieselgel 60, 100 g) using ether as the eluent, to give the titlecompound as a colourless gum (1.08 g) which darkened to a brown gum onstorage. This material failed to crystallise from common organicsolvents.

Analysis. Found: C,65.8; H,6.4; N,14.7. C₁₅ H₇ N₃ O₂.O.25H₂ O requires:C,65.3; H,6.4; N,15.2%.

(ii) 2-Methylpropyl [3-(2-aminoethyl)-1H-indol-5-yl]carbamate,hydrochloride

A solution of 2-methylpropyl [3-(cyanomethyl)-1H-indol-5-yl]carbamate,quarter hydrate (0.5 g) in absolute ethanol (30 ml) containingconcentrated hydrochloric acid (8 drops) was hydrogenated at roomtemperature and pressure over palladium on charcoal (10%, 1 g) for 24 hbefore the catalyst was replaced (10%, 0.5 g). After a further 4 h whenhydrogen uptake ceased (90 ml) the catalyst was filtered off, washedwith absolute ethanol, and the filtrate evaporated in vacuo giving apink solid. The crude hydrochloride was crystallised from a mixture ofmethanol and ethyl acetate, to give the title compound as a white solid(0.15 g) m.p. 258°-260°.

Analysis. Found: C,57.7; H,7.0; N,13.1. C₁₅ H₂₁ N₃ O₂.HCl requires:C,57.8; H,7.1; N, b 13.5%.

Example 14 N-[3-(2-Aminoethyl)-1H-indol-5-yl]-N',N'-dimethylsulphamide,maleate.

(i) N-[3-(Cyanomethyl)-1H-indol-5-yl]-N',N'-dimethylsulphamide

Dimethyl sulphamoyl chloride (1.2 ml) was added dropwise to a stirredsolution 5-amino-1H-indole-3-acetonitrile (1.7 g) in drydimethyl-formamide (50 ml) containing triethylamine (2.8 ml). After 3 h,the resulting suspension was diluted with water (20 ml) and stirred for30min. The resulting solution was poured into water (100 ml) andextracted with ethyl acetate (2×100 ml). The combined organic extractswere washed with water (100 ml) and brine (2×100 ml), dried (Na₂ SO₄)and evaporated in vacuo, to give a dark brown oil which was purified bycolumn chromatography (Kieselgel 60, 100 g) eluted with ether/ethylacetate, (9:1) to give the title compound as white solid (0.75 g) m.p.147°-150°.

(ii) N-[3-(2-Aminoethyl)-1H-indol-5-yl]-N',N'-dimethylsulphamide,maleate

A solution of N-[3-(cyanomethyl)-1H-indol-5-yl]-N',N'-dimethylsulphamide(0.3 g) in absolute ethanol (50 ml ) containing concentratedhydrochloric acid (6 drops) was hydrogenated at room temperature andpressure over palladium on charcoal (10%, 0.2 g) for 24 h before thecatalyst was replaced (10%, 0.5 g). After a further 4 h, when hydrogenuptake ceased (60 ml) the catalyst was filtered off, washed withethanol, and the filtrate evaporated in vacuo to give a brown oil. Theoil was then partitioned between ethyl acetate (2×20 ml) and 2N sodiumcarbonate (10 ml), the combined organic extracts dried (Na₂ SO₄) andevaporated in vacuo to give a fawn foam. The foam was dissolved in asolution of maleic acid (0.16 g) in methanol (4 ml) and the maleateprecipitated by the addition of ethyl acetate (100 ml) and ether (150ml). The salt was crystallised from a mixture of methanol and ethylacetate to give the title compound (0.6 g) as a fawn solid m.p.138°-142°.

Analysis. Found: C,48.3; H,5.5; N,13.8. C₁₂ H₁₈ N₄ O₂ S.C₄ H₄ O₄requires: C,48.2; H,5.6; N,14.1%.

PHARMACEUTICAL EXAMPLES Tablets

These may be prepared by direct compression or wet granulation. Thedirect compression method is preferred but may not be suitable in allcases as is dependent upon the dose level and physical characteristicsof the active ingredient.

    ______________________________________                                        A. Direct Compression                                                                            mg/tablet                                                  ______________________________________                                        Active ingredient    10.0                                                     Microcrystalline Cellulose B.P.C.                                                                  89.5                                                     Magnesium Stearate    0.5                                                                          100.0                                                    ______________________________________                                    

The active ingredient is sieved through a 250 μm sieve, blended with theexcipients and compressed using 6.0 mm punches. Tablets of otherstrengths may be prepared by altering the compression weight and usingpunches to suit.

    ______________________________________                                        B. Wet Granulation                                                                               mg/tablet                                                  ______________________________________                                        Active ingredient    10.0                                                     Lactose B.P.         74.5                                                     Starch B.P.          10.0                                                     Pregelatinised Maize Starch B.P.                                                                    5.0                                                     Magnesium Stearate B.P.                                                                             0.5                                                     Compression Weight   100.0                                                    ______________________________________                                    

The active ingredient is sieved through a 250 μm sieve and blended withthe lactose, starch and pregelatinised starch. The mixed powders aremoistened with purified water, granules are made, dried, screened andblended with the Magnesium Stearate. The lubricated granules arecompressed into tablets as described for the direct compressionformulae.

The tablets may be film coated with suitable film forming materials,e.g. methyl cellulose or hydroxy-propyl methyl cellulose using standardtechniques. Alternatively the tablets may be sugar coated.

    ______________________________________                                        Capsules           mg/capsule                                                 ______________________________________                                        Active ingredient  10.0                                                       *Starch 1500       89.5                                                       Magnesium Stearate B.P.                                                                           0.5                                                       Fill Weight        100.0                                                      ______________________________________                                         *A form of directly compressible starch supplied by Colorcon Ltd.,            Orpington, Kent.                                                         

The active ingredient is sieved through a 250 μm sieve and blended withthe other materials. The mix is filled into No. 2 hard gelatin capsulesusing a suitable filling machine. Other doses may be prepared byaltering the fill weight and if necessary changing the capsule size tosuit.

    ______________________________________                                        Syrup           mg/5 ml dose                                                  ______________________________________                                        Active ingredient                                                                              10.0                                                         Sucrose B.P.    2750.0                                                        Glycerine B.P.   500.0                                                        Buffer                                                                        Flavour                                                                       Colour              as required                                               Preservative                                                                  Distilled Water 5.00 ml                                                       ______________________________________                                    

The active ingredient, buffer, flavour, colour and preservative aredissolved in some of the water, and the glycerine is added. Theremainder of the water is heated to 80° C. and the sucrose is dissolvedin this and cooled. The two solutions are combined, adjusted to volumeand mixed. The syrup produced is clarified by filtration.

    ______________________________________                                        Suppositories                                                                 ______________________________________                                        Active ingredient                                                                              10.0        mg                                               *Witepsol H15 to 1.0         g                                                ______________________________________                                         *A proprietary grade of Adeps Solidus ph. Eur.                           

A suspension of the active ingredient in the matter Witepsol H15 isprepared and filled using a suitable machine into lg size suppositorymoulds.

    ______________________________________                                        Injection for Intravenous Administration                                                        % w/v                                                       ______________________________________                                        Active ingredient    0.20                                                     Water for injections B.P. to                                                                      100.00                                                    ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted to that of maximum stability and/or to facilitatesolution of the active ingredient using dilute acid or alkali or by theaddition of suitable buffer salts.

The solution is prepared, clarified and filled into appropriate sizedampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen.

    ______________________________________                                        INHALATION CARTRIDGES                                                                          mg/cartridge                                                 ______________________________________                                        Active ingredient micronised                                                                     1.00                                                       Lactose B.P.       39.0                                                       ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range prior to blending with normal tabletting gradelactose in a high energy mixer. The powder blend is filled into No. 3hard gelatin capsules on a suitable encapsulating machine. The contentsof the cartridges are administered using a powder inhaler (e.g. GlaxoRotahaler).

    ______________________________________                                        METERED DOSE PRESSURISED AEROSOL                                                             mg/metered dose                                                                           Per can                                            ______________________________________                                        Active ingredient micronised                                                                   0.500         120    mg                                      Oleic Acid B.P.  0.050         12     mg                                      Trichlorofluoromethane B.P.                                                                    22.25         5.34   g                                       Dichlorodifluoromethane B.P.                                                                   60.90         14.62  g                                       ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range. The Oleic Acid is mixed with theTrichlorofluoromethane at a temperature of 10°-15° C. and the microniseddrug is mixed into this solution with a high shear mixer. The suspensionis metered into aluminum aerosol cans and suitable metering valves,delivering a metered dose of 85 mg of suspension are crimped onto thecans and the Dichlorodifluoromethane is pressure filled into the cansthrough valves.

We claim:
 1. A compound of formula (I): ##STR11## wherein R₁ representsa group CHO, COR₈, CO₂ R₈, CONR₉ R₁₀, CSNR₉ R₁₀ or SO₂ NR₉ R₁₀, where R₈represents C₁₋₆ alkyl optionally substituted by 1-3 halogen atoms; cycloC₅₋₇ alkyl, phenyl, phenyl C₁₋₄ alkyl, wherein said phenyl groups areunsubstituted or substituted by one or more C₁₋₆ alkyl groups, halogenatoms, hydroxy or C₁₋₆ alkoxy groups;R₉ represents a hydrogen atom or aC₁₋₆ alkyl group, and R₁₀ represents a hydrogen atom or a C₁₋₆ alkyl,cyclo C₅₋₇ alkyl, phenyl or phenyl C₁₋₄ alkyl group wherein said phenylgroups are unsubstituted or substituted by one or more C₁₋₆ alkylgroups, halogen atoms, hydroxy or C₁₋₆ alkoxy groups; R₂, R₄, R₆ and R₇,which may be the same or different, each represents a hydrogen atom or aC₁₋₃ alkyl group; R₅ represents a hydrogen atom or a C₁₋₆ alkyl, cycloC₅₋₇ alkyl, C₃₋₆ alkenyl, or a phenyl C₁₋₄ alkyl group, wherein saidphenyl group is unsubstituted or substituted by one or more C₁₋₆ alkylgroups, halogen atoms, hydroxy or C₁₋₆ alkoxy groups; and Alk representsan alkylene chain containing two or three carbon atoms which may beunsubstituted or substituted by not more than two C₁₋₃ alkyl groups;with the provisos that when R₄ and R₅ both represent alkyl groups R₁does not represent the group CHO or COR₈ and that when R₄, R₅, R₆ and R₇all represent hydrogen R₁ does not represent the group SO₂ NH₂ ; andphysiologically acceptable salts and solvates thereof.
 2. A compoundaccording to claim 1, wherein Alk represents an unsubstituted alkylenechain containing two carbon atoms.
 3. A compound according to claim 1,wherein R₄ and R₅, which may be the same or different, each represents ahydrogen atom or a methyl or ethyl group.
 4. A compound according toclaim 1, wherein R₂ represents a hydrogen atom or a methyl group.
 5. Acompound according to claim 1, having the formula (Ia): ##STR12##wherein R_(1a) represents a group CHO, CONH₂, COR_(8a) or CO₂ R_(8a),whereR_(8a) is an alkyl group containing 1 to 4 carbon atoms or atrifluoromethyl group; R_(2a) represents a hydrogen atom or a methylgroup; and R_(4a) and R_(5a), which may be the same or different, eachrepresents a hydrogen atom or a methyl or ethyl group with the provisosthat the total number of carbon atoms in R_(4a) and R_(5a) together doesnot exceed two, that when R_(1a) represents a group CHO or a groupCOR_(8a) then R_(4a) represents a hydrogen atom, and physiologicallyacceptable salts and solvates thereof.
 6. A compound according to claim1, having the formula (Ib): ##STR13## wherein R_(1b) represents a groupCHO, CONH₂ or CO₂ R_(8b) whereR_(8b) is a methyl, ethyl or isobutylgroup; R_(2b) represents a hydrogen atom or a methyl group; and R_(4b)and R_(5b), which may be the same or different, each represents ahydrogen atom or a methyl or ethyl group with the provisos that thetotal number of carbon atoms in R_(4b) and R_(5b) together does notexceed two and that when R_(1b) is the group CHO, R_(4b) represents ahydrogen atom, and physiologically acceptable salts and solvatesthereof.
 7. A compound according to claim 1, wherein the physiologicallyacceptable salt is a hydrochloride, hydrobromide, sulphate, fumarate ora maleate.
 8. A method of treating a patient suffering from migrainewhich comprises administering to the patient an effective amount of acompound of formula (I) as defined in claim 1 or a physiologicallyacceptable salt or solvate thereof.
 9. A compound selected from thegroup consisting of ethyl [3-(2-aminoethyl)-1H-indol-5-yl]carbamate,2-methylpropyl [3-(2-amino-ethyl)-1H-indol-5-yl]carbamate andphysiologically acceptable salts and solvates thereof.
 10. Apharmaceutical composition comprising an effective amount for thetreatment of migraine of a compound of formula (I) of claim 1 or aphysiologically acceptable salt or solvate thereof together with aphysiologically acceptable carrier or excipient.